Since the introduction of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for patients with lung cancer, we have seen a subset of patients do remarkably well, with dramatic and long lasting responses. Unfortunately, within a few months of those impressive responses, we learned that people invariably develop acquired resistance to these agents.

One of the challenges we face now when a patient with a "driver mutation" like an EGFR mutation or an ALK rearrangement develops progression on a targeted therapy against that particular target is whether to continue on another agent that might work specifically against that target or switch to a less specific approach, like chemotherapy or immunotherapy, which haven't been demonstrated to be more or less effective against a specific molecularly defined subgroup.

With the recent approval of afatinib, now becoming commercially available as Gilotrif, there is the potential new strategy for patients with an EGFR mutation who develop acquired resistance to a different EGFR tyrosine kinase inhibitor (TKI) in an earlier line of therapy.

Dr. Bob Doebele from the University of Colorado, offers his insights on how to approach a patient with gradual progression in a single site, especially in the brain, or more multifocal progression after a good initial response to a targeted agent.

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Drs. Jack West, Mary Pinder, and Nate Pennell discuss options for managing acquired resistance to EGFR TKIs and ALK inhibitors in patients with advanced NSCLC and a driver mutation.

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Dr. Mary Pinder reviews promising studies from ASCO 2013 on second gen. ALK inhibitors LDK-378, CH5424802, and AP26113 in patients with ALK-positive advanced NSCLC, including impressive activity in crizotinib-refractory patients and those with brain mets.

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Dr. Phil Bonomi, from Rush University, offers his insights on how to approach a patient with gradual progression in a single site, especially in the brain, or more multifocal progression after a good initial response to a targeted agent.

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Dr. David Spigel, Sarah Cannon Cancer Center, offers his insights on how to approach a patient with gradual progression in a single site, especially in the brain, or more multifocal progression after a good initial response to a targeted agent.

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Dr. Karen Kelly, of the University of California, Davis, provides her thoughts on whether to continue an effective treatment beyond 4-6 cycles in an effort to exhaust the possible benefit from that treatment.

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Dr. Sarah Goldberg, from Yale Cancer Center, offers her insights on how to approach a patient with gradual progression in a single site, especially in the brain, or more multifocal progression after a good initial response to a targeted agent.

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